Key Clinical Summary: BRAF-driven treatment decisions - First line personalization and adverse events management

This is a micro-learning module summary of Dr. Zev Wainberg’s session which you can find here. Before participating, please read our CME and disclosure information which can be found here.

Acknowledgment: This program is supported by an educational grant from Pfizer. It is designed only for healthcare professionals in the United States.

Introduction

This summary explores recent developments in BRAF-targeted therapies for advanced disease, outlining the evolving treatment landscape, the rationale for integrating targeted agents with chemotherapy (ChT) in the frontline setting, and emerging evidence from pivotal clinical trials. It reviews the clinical relevance of BRAF alterations and key efficacy and safety outcomes for combination regimens.

Clinical Relevance of BRAF in mCRC

• BRAF V600E–mutated mCRC represents a distinct molecular and clinical subset, accounting for approximately 8% of stage IV disease. Although the prevalence may be slightly higher in earlier-stage tumors, the defining feature across settings is its aggressive behavior and poor prognosis relative to other molecular subtypes.
• These tumors typically arise in the right colon, present with bulky primary masses, and are commonly associated with poor differentiation and mucinous histology. A minority exhibit mismatch-repair deficiency (dMMR; 15–20%)
• Beyond V600E – the dominant actionable subtype – other non-V600E BRAF mutations are less responsive to currently available targeted therapies, underscoring the importance of accurate classification.

Biomarker Testing and Diagnostic Considerations

• Standard BRAF mutation testing should be carried out at the time of diagnosis of metastatic disease
• The choice of testing modality has broadened from traditional polymerase chain reaction (PCR)-based assays to next-generation sequencing (NGS), which is increasingly favored because it identifies the full spectrum of BRAF mutations
• Liquid biopsy is also emerging as a reliable alternative, with concordance rates of >90% between circulating tumor DNA and tissue-based testing supporting its clinical utility
• Early identification of BRAF mutation status is essential, as it directly influences first-line treatment selection and facilitates timely initiation of targeted approaches

Historical Treatment Approaches in mCRC and Their Limitations

• Prior to targeted therapy availability, the poor prognosis associated with BRAF V600E–mutated mCRC prompted exploration of intensified ChT regimens
• Early signals of benefit came from analyses of triplet regimens such as FOLFOXIRI plus bevacizumab, with some studies suggesting improved outcomes compared with doublet ChT
• However, meta-analyses ultimately yielded inconclusive results, and the modest and inconsistent benefits of ChT intensification led to a shift toward combinations incorporating targeted agents

The BREAKWATER Trial

• A pivotal step in the evolution of frontline therapy for BRAF V600E–mutated mCRC came with the BREAKWATER trial, a randomized phase III study evaluating encorafenib (a selective BRAF inhibitor) plus cetuximab (an EGFR inhibitor)
• The study initially included three arms:

1. Arm A: Encorafenib + cetuximab
2. Arm B: Encorafenib + cetuximab + mFOLFOX6
3. Arm C: ChT ± bevacizumab (standard of care [SoC])

• An early safety lead-in demonstrated encouraging tolerability and activity across both ChT cohorts, while the arm consisting of encorafenib and cetuximab without ChT was closed early when comparative data indicated inferiority relative to the triplet regimen. The study therefore continued with a two-arm randomization: triplet therapy versus SoC.

Efficacy Outcomes

• The combination of encorafenib, cetuximab, and mFOLFOX6 significantly improved key efficacy endpoints:
• Overall response rate (ORR): The triplet regimen achieved an ORR of 66% by blinded independent review, compared with 37% for the SoC. Dual targeted therapy without ChT produced an ORR of 46%, reinforcing the added value of cytotoxic backbone integration
• Progression-free survival (PFS): Median PFS improved from 7 months with standard ChT to 13 months with triplet therapy, meeting the co-primary endpoint with statistical significance
• Overall survival (OS): Interim analyses demonstrated a doubling in median OS; 30 months with triplet therapy versus 15 months with the SoC, corresponding to a hazard ratio of 0.49 (95% confidence interval 0.375–0.632; p<0.0001)
• These results led to regulatory approval of encorafenib plus cetuximab in combination with FOLFOX as a frontline option for BRAF V600E–mutated mCRC

Safety Outcomes

• The safety profile of the triplet regimen was manageable and consistent with the known toxicities of its components
• Compared with the SoC, higher rates of anemia, vomiting, arthralgia, asthenia, pyrexia and rash were observed with the encorafenib + cetuximab + mFOLFOX6 triplet, although these were mostly grade 1–2

Conclusion

BRAF V600E–mutated mCRC is a distinct, high-risk subset requiring early and accurate molecular testing to guide therapy. The emergence of targeted combinations, culminating in the BREAKWATER trial’s demonstration of substantial improvements in response, PFS, and OS with encorafenib, cetuximab, and mFOLFOX6, has markedly changed the therapeutic landscape. These advances offer meaningful clinical benefit and establish a new SoC for this historically refractory population.

Content is accurate as of the date of release on 6 January 2026.